Hyper IgM Syndrome (Hyperimmunoglobulin M Syndromes)

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Hyper IgM Syndrome
Body Parts: Whole Body
Medical Subjects: Children's Health Genetic disease
Overview

What Is Hyper IgM Syndrom?

What is Hyper IgM Syndrom?

Hyper IgM Syndrom, also known as high immunoglobulin M syndrome, is a group of diseases with elevated (or normal) serum IgM accompanied by decreased levels of other immunoglobulins (IgA, IgG, and IgE) for various reasons, and the patients may present with low resistance and easy infection.

What conditions can cause an increase in serum IgM?

A range of genetic disorders, congenital rubella syndrome, T cell leukemia or lymphoma, and even oral phenytoin sodium can cause an increase in blood IgM.

What are the most common types of hyper igm synthes?

  • CD40L defect (hyper igm syndrome type 1)
  • CD40 defect (hyper igm syndrome type 3)
  • AID defect (hyper igm syndrome type 2)
  • UNG defect (hyper igm syndrome type 5)
  • Hyper IgM Syndrom4 type 4.

Is hyper igm synthes common?

Hyper IgM Syndrom is a rare condition. The incidence of CD40L defects is two parts per million. The exact onset data for AID defects are unknown, but are estimated at one in a million. CD40 defects and UNG defects are only reported on a case by case basis.

Cause

What Is The Cause Of Hyper IgM Syndrome?

What is the cause of Hyper IgM Syndrom?

A range of genetic disorders, congenital rubella syndrome, T cell leukemia or lymphoma, and even oral phenytoin sodium can cause an increase in blood IgM.

What genetic conditions can cause Hyper IgM Syndrome?

  • Activated phosphatidylinositol 3-kinase syndrome (activated PI3K-δ syndrome).
  • PMS2 defect.
  • MutS homolog 6(Mutator S homolog 6, MSH6) defect.
  • Ataxia telangiectasia.
  • Nijmegen fracture syndrome.
  • Common variant immunodeficiency disease.
  • CD40L deficiency, also known as hyperIgM syndrome type 1.
  • CD40 deficiency, also known as hyperIgM syndrome type 3.
  • Activated-induced cytidine deaminase (AID) deficiency, also known as hyperIgM syndrome type 2.
  • Uracil N- glycosylase (UNG) deficiency, also known as hyperIgM syndrome type 5.
  • Downstream of DNA cleavage in the switch (S) region, there was a defect of class switch recombination.
  • High IgM syndrome type 4 with unknown molecular basis.

How is Hyper IgM syndrome inherited?

The most common form of hyperIgM syndrome is CD40L deficiency, which follows the X-linked recessive inheritance rule, that is, women carrying the causative gene generally do not develop the disease, while men carrying the causative gene do.

The second most common form of hyperIgM syndrome is AID deficiency, which generally follows autosomal recessive inheritance.

The UNG defect and the CD40 defect are also autosomal recessive. That is to say, people who carry two disease-causing genes only get sick.

Symptom

What Is The Symptoms Of Hyper IgM Syndrome?

What are the manifestations of Hyper IgM Syndrome type 1 or Hyper IgM Syndrome type 3?

  • Patients with HyperIgM Syndrome type 1 or HyperIgM Syndrome type 3 share similar characteristics and lead to both humoral and cellular immunodeficiency, known as "combined immunodeficiency". Manifested as:
  • Recurrent sinus and lung infection, that is, prone to repeated pneumonia, sinusitis, otitis media.
  • About one-third of patients develop chronic diarrhea that begins in infancy and is repeated over time.
  • It is prone to sclerosing cholangitis, liver cirrhosis, and cholangiocarcinoma, and it can occur in childhood, possibly related to cryptosporidium parvum and cytomegalovirus infection.
  • Cryptococcus, Toxoplasma gondii, JC virus and other infections are likely to occur, resulting in nervous system lesions, such as meningoencephalitis and progressive multifocal leukoencephalopathy.
  • Cellulitis, sepsis, osteomyelitis, and aphthous stomatitis are common occurrences.
  • It is prone to gastrointestinal tract and peripheral nerve ectodermal tumor of pancreas, as well as the aforementioned liver cancer and cholangiocarcinoma.
  • Childhood osteoporosis may occur, leading to a predisposition to fractures.
  • It is prone to autoimmune diseases, leading to inflammatory bowel disease and cytopenia.
  • Lack of antibody response to protein (tetanus, diphtheria, and Haemophilus influenzae type b) and polysaccharide (streptococcus pneumoniae) antigens suggests that these vaccines do not confer resistance to the corresponding disease.

What are the manifestations of Hyper IgM Syndrome type 2?

Hyper IgM syndrome type 2 is mainly caused by humoral immune deficiency.

As it does not cause cellular immunodeficiency, lymphoid tissue deficiency such as absent tonsil due to CD40L deficiency does not occur. Hyper IgM syndrome type 2 manifestations are:

  • Recurrent sinus and lung infection, that is, prone to repeated pneumonia, sinusitis, otitis media.
  • It is easy to cause bronchiectasis due to repeated infection.
  • Meningitis, cellulitis, lymphadenitis and gastrointestinal infections are common.
  • It can be caused by lymphoid hyperplasia, such as abnormally large tonsils.
  • About 20% of patients have autoimmune diseases that cause cytopenia, hepatitis, inflammatory bowel disease, and arthritis.
  • Lack of antibody response to protein (tetanus, diphtheria, and Haemophilus influenzae type b) and polysaccharide (streptococcus pneumoniae) antigens suggests that these vaccines do not confer resistance to the corresponding disease.

What are the manifestations of Hyper IgM Syndrome type 4 and type 5?

Hyper IgM syndrome type 5 is similar to hyper IgM syndrome type 2. Hyper IgM syndrome type 4 is also similar to hyper IgM syndrome type 2, but is slightly less severe.

Detect

How To Check Hyper IgM Syndrome?

What are the abnormal results of hyper IgM syndrome type 1 or hyper IgM syndrome type 3 during laboratory tests?

  • Serum IgG, IgE levels were significantly reduced (but children under 4 months of age could have IgG from the mother, so the reduction in IgG could not be significant).
  • Serum IgM levels were normal or elevated (approximately 50% of patients with CD40L deficiency had normal or even decreased serum IgM levels).
  • Serum IgA levels were significantly decreased (IgA serum levels were normal in patients with occasional CD40L defects).
  • The total number of B lymphocytes was normal, but memory (CD27+)B lymphocytes were significantly reduced, and there was a lack of switching memory (IgD-CD27+)B lymphocytes.
  • Two-thirds of patients with CD40L deficiency had neutropenia, 15%–32% had anemia, and 4% had thrombocytopenia.
  • Dendritic cell/monocyte defects are also present in patients with CD40 deficiency.

What are the abnormal results of hyper IgM syndrome type 2 or hyper IgM syndrome type 5 during laboratory tests?

  • Serum IgG, IgA, and IgE levels were significantly reduced (but children under 4 months of age could have IgG from the mother, so IgG could not be significantly reduced).
  • Serum IgM levels were normal or elevated.
  • The total number of B lymphocytes was normal, but memory (CD27+)B lymphocytes were significantly reduced, and there was a lack of switching memory (IgD-CD27+)B lymphocytes.

What are the abnormal results of hyper IgM syndrome type 4 during laboratory tests?

This is similar to AID deficiency and UNG deficiency, but the ability to produce IgG remains, so the decline in IgG is not obvious.

How to diagnose hyper IgM syndrome type 1?

A preliminary diagnosis of hyper IgM syndrome due to CD40L deficiency can be made in men who have a reduced serum IgG level and a normal or elevated serum IgM level in combination with opportunistic infections.

Further diagnosis requires:

  • For infants up to 6 months of age, genetic testing is required to confirm the diagnosis. Because children of this age group will have varying degrees of decreased CD40L expression in CD4+ lymphocytes.
  • In older children, the diagnosis can be confirmed by immunoanalysis, which reveals impaired CD40L expression on the surface of CD4+ T cells during in vitro activation.
  • Genetic testing is also needed to confirm the diagnosis in patients with high clinical suspicion of CD40L deficiency but normal anti-CD40L monoclonal antibody staining.

Based on the genetic characteristics of the CD40L defect, women generally do not have a CD40L defect. CD40 deficiency should be considered in females who present with reduced serum IgG levels and normal or elevated serum IgM levels, combined with opportunistic infections.

How to diagnose hyper IgM syndrome type 3?

When a patient has a reduced serum IgG level and a normal or elevated serum IgM level combined with opportunistic infection and suspects a CD40L/CD40 defect, further diagnosis requires:

  • Because women generally do not have CD40L defects, they only need to use flow cytometry to detect whether CD40 is expressed.
  • For males, flow cytometry should be used to detect the expression of CD40 after confirming that CD40L is normal (see the previous question for the determination method).
  • A very small number of patients with CD40 expression by flow cytometry but high clinical suspicion of CD40 deficiency require genetic testing to confirm the diagnosis.

How to diagnose hyper IgM syndrome type 2 and hyper IgM syndrome type 5?

Rely on genetic testing to confirm the diagnosis.

How to diagnose hyper IgM syndrome type 4?

There is no diagnostic test yet, and the diagnosis is mainly based on excluding the possibility of other genetic defects.

Prevention

How To Prevent Hyper IgM Syndrome?

Can hyper IgM syndrome be prevented?

For individuals with a family history of hyper IgM syndrome, genetic counseling is recommended to predict the likelihood of future generations and to try to avoid the birth of a child with hyperIgM syndrome before birth preparation.

Treatment

How To Treat Hyper IgM Syndrome?

What department should you visit for hyper IgM syndrome?

Department of rheumatology immunology, department of infection.

How to treat Hyper IgM Syndrome?

The first is to be alert to infections and other complications, and treat them as soon as possible when they are found. Therefore it is recommended:

  • Liver function should be checked once every 4–6 months and liver ultrasound should be checked at least once a year for early detection of liver complications.
  • Fecal cryptosporidium and microsporidia were tested every 6 months by PCR and infection was detected early and azithromycin and nitazoxanide were used as soon as possible to prevent progression of the infection.

Due to the prevalence of humoral immune deficiencies in patients, it is recommended that:

  • Human immunoglobulin was infused every 3–4 weeks at 400–600 mg/kg body weight each time. The interval should not exceed 4 weeks, but does not need to be less than 2 weeks.
  • Prevention of infection by long-term oral administration of compound sulfamethoxazole. Prophylactic antibiotic therapy for chronic complications including bronchiectasis, recurrent sinusitis, etc. is necessary in patients with AID deficiency, UNG deficiency, and type 4 hyperIgM syndrome without cellular immunodeficiency.
  • Subcutaneous injection of recombinant human granulocyte colony-stimulating factor to treat chronic severe neutropenia or severe infection.
  • Recombinant CD40L for treatment of cryptosporidiosis of the biliary tract.

Patients with CD40L or CD40 deficiency can also undergo hematopoietic stem cell transplantation to eradicate the disease, especially in younger patients without liver disease and undergoing myeloablative pretreatment.

Early hematopoietic stem cell transplantation can prevent the development of chronic liver disease.

What is the therapeutic effect of hyper IgM syndrome?

Patients with CD40L or CD40 deficiency have both humoral and cellular immunodeficiency. However, pure human immunoglobulin infusion therapy can only improve humoral immunodeficiency and is not helpful for the patient's existing cellular immunodeficiency.

Therefore, the best strategy at present is early hematopoietic stem cell transplantation in the absence of chronic liver disease, with a relatively good prognosis.

Patients with AID deficiency and UNG deficiency had only humoral immunity deficiency. Therefore, with human immunoglobulin input and active anti-infective therapy, prevention is good.

Life

What Should Patients With Hyper IgM Syndrome Pay Attention To In Life?

Mainly according to the doctor' s advice regular review, and try to avoid all kinds of infection. Such as pay attention to personal hygiene; For example, do not bathe in rivers, lakes, or pools that are not disinfected with chlorine to minimize cryptosporidium infection.

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